WHO Draft Rapid Response + Containment, May 2006

Projected Outbreak of H5N1 in Thailand Red = new cases. Green = areas where the epidemic has finished. Ferguson et al. Nature 437:209, 2005 R 0 = 1.5

Left: uncontrolled outbreak. Red = new cases. Green = areas where the epidemic has finished. Above: Controlled outbreak. Red = areas of infection. Blue = areas where a combination of control measures implemented. Projected Outbreak of H5N1 Influenza in Thailand

Elimination of a pandemic virus at its source? Ring chemoprophylaxis feasible if: –Geographically targeted in non-urban setting –Early intervention within 1-3 wks –Virus of low-moderate transmissibility (R 0 < 1.8) –Chemoprophylaxis of % of population –High compliance –Movement restrictions; social distancing Maximum of 1-3 million courses needed –300,000 may be sufficient Ferguson et al. Nature 437:209, 2005

Rapid Response: Antiviral Deployment Rapid use of antiviral prophylaxis is key component. Mass targeted antiviral prophylaxis: –Goal of 90% coverage –Geographic radius of 5-10 km from each detected case OR –Administrative area of “at-risk” population of 10-50,000 Multiple logistical hurdles –WHO donation of 3.0 M courses –440 courses = 7.8 kg –100,000 courses = 19 shipping pallets –Start dispensing within 12 hrs of receipt WHO Draft Rapid Response + Containment Document, May 2006

Antiviral Resistance in Influenza Viruses M2 inhibitors: –Primary resistance in epidemic (>90% of recent H3N2) or pandemic virus possible; frequent with Rx –Confers cross-resistance to entire class –Resistant variants virulent and transmissible NA inhibitors: –No primary resistance; active for all 9 NA types –Inhibitory for M2 resistant-variants –Variable NAI cross-resistance depending on type/subtype and drug –Most NAI resistance causes  infectivity and virulence in animals NISN. Weekly Epi Record 33:306, 2004

Detection Of Antiviral Resistant Influenza During Treatment Frequency of resistance OseltamivirM2 inhibitor Out-patient adults Out-patient children 0.4% 5.5% ~30% Inpatient children 18% 80% Immunocompromised ?>33% Roberts N. Phil Trans R Soc Lond 356:1895, 2001 Kiso et al. Lancet 364: 759, 2004

Pharyngeal Viral Loads during Oseltamivir Treatment of H5N1 de Jong et al. NEJM 353:25, 2005

Neuraminidase Inhibitor Treatment : Antiviral Resistance Emergence of oseltamivir-resistant variants may be associated with prolonged viral detection in A/H3N2-infected children and in H5N1-infected patients. –Resistance due to H274Y mutation may compromise clinical efficacy in some H5N1 patients. No transmission of oseltamivir-resistant variants detected in house-hold based studies or in prophylaxis failures to date. –Some resistant variants are transmissible in ferret model (including H274Y mutation in N1)

Influenza Prevention In Households: PEP Antiviral (Study) No. Contacts (age) Reduction in 2° influenza illness Reduction in influenza infection Oseltamivir (Welliver et al, 2000) 955 (13+ yr) 89% 49% Oseltamivir* (Hayden et al, 2004) 792 (1+ yr) 73%35% (Index +) Zanamivir* (Hayden et al, 2000) 837 (5+ yr) 79% 62% Zanamivir (Monto et al, 2002) 1,291 (5+ yr) 82% 59% *Index case given treatment

Interval from PEP Initiation to Secondary Illness Onset in Household Contacts (N = 1,291) Note: zanamivir PEP started < 36 hr of index illness onset Monto et al. JID 186:1582, 2002

Influenza Post-exposure Prophylaxis (PEP) with Neuraminidase Inhibitors: Summary Socially targeted antiviral prophylaxis (PEP) is highly effective in protecting contacts in households during seasonal influenza. – Reductions in illness > infection. –Secondary cases occur early, often in first few days after index case recognition. – Rapid initiation is essential. Inhaled zanamivir is also effective for prevention. –Unstudied in human H5N1 infections to date.

Pandemic Vaccine Production Produce in existing facilities Produce with existing technologies Define the most antigen-sparing formulation for a vaccine that will be acceptably immunogenic for a population –Develop formulation that can be used by all influenza vaccine companies Goal is to make largest number of doses of an affordable pandemic vaccine can be produced worldwide. Immunologically naïve individuals will likely require two doses of an adjuvanted, inactivated vaccine. Fedson. J Public Health Policy 2005; 26:4-29

Dose Selection Considerations for Non- adjuvanted H5N1 Vaccine  g HA per dose % with Neut titer  1:40 Number Vaccinated Number protected

Neuraminidase Inhibitor Prophylaxis Long-term prophylaxis (4-6 weeks) is highly protective against seasonal influenza illness (efficacy ~ 85-90%). Short-term prophylaxis (7-10 days) is protective against influenza illness in household contacts (efficacy ~ 70-90%). Protection is likely to be somewhat lower for H5N1 or another novel strain. Illness will occur despite prophylaxis. If someone develops illness on prophylaxis, increase dose to full therapeutic one.

Antivirals for H5N1: Conclusions Multiple potential reasons exist for treatment failure, but viral clearance is associated with favorable prognosis. Oseltamivir is preferred agent for treatment. – uidelines/pharmamanagement/en/index.html –Appropriate dose regimen and duration for H5N1 are uncertain. –Antiviral resistance with H274Y mutation may compromise efficacy in some patients. –No clinical data are available for inhaled zanamivir at present.

Pharyngeal Viral Loads during Oseltamivir Treatment of H5N1 de Jong et al. NEJM 353:25, 2005

Human Seasonal Vaccine Only 300 million trivalent vaccine doses produced annually from eggs for global market. – Strains made available from WHO Global Surveillance Network Production and consumption highly localized – >95% produced in nine countries (>65% in Europe) – 12% of population use 62% of vaccine Production matches demand (i.e., market driven) – Very little surge capacity, needs lead time of at least six months – Increased seasonal demand enhances production capacity

Influenza pandemic vaccines Lag between detection of pandemic strain and full scale vaccine production – Optimistic approach Vaccine prototype development 1-2 month Clinical batch production and testing 1-2 month Vaccine production 2 month ~ million?

Pandemic Vaccine Lessons from 1957, 1968, & 1977 Unprimed subjects require 2 doses. Differences exist in immunogenicity between subtypes. Whole virus is usually but not always more immunogenic and reactogenic. –Children have more side effects Adjuvants are useful and can spare antigen in unprimed persons. Efficacy may be unpredictable.

Immunogenicity of Candidate H5N1 Vaccines in Healthy Adults Vaccine type (N)RouteHA dose (µg) % Neut titer > 1:40 Sub-virion, egg- grown, non- adjuvanted X 2 (N=451) IM Treanor et al. NEJM 354:1343, 2006

H5 Vaccines: Summary Inactivated H5N1 vaccines are safe and immunogenic. –Reverse genetics enables rapid generation of seed viruses with attenuated virulence. Unadjuvanted H5 appears to be a poor human immunogen. –Alum is somewhat effective as an adjuvant. Two doses of an adjuvanted H5 vaccine will likely be required. –Current capacity for 30 ug doses  250 M person in 1st year